Reinventing Gene Editing for Safer, More Precise Therapies

Amanda Smith, PhD, is the CEO of Pencil Biosciences, an early-stage biotechnology company reimagining gene editing by building novel editors from the ground up. Prior to leading Pencil, she held scientific, intellectual property, and innovation roles across academia, pharma, and biotech, including positions at a U.K.-based gene editing company, Horizon Discovery (now part of Revvity), and Sanofi. Today, she is focused on creating safer, more precise, and versatile gene editing tools that have the potential to expand the reach of genetic medicine.

Smith recently spoke with Damian Doherty, Editor in Chief of Inside Precision Medicine about the limitations of current gene editing technologies, Pencil’s modular, break-free approach, and how this new generation of editors could expand and transform the impact of genetic medicine.

Q: Tell us a bit about your own background. What experience shaped your approach to leading a company at the frontier of gene editing? 

Smith: From a young age I was fascinated by life science and biology, and I began my career as an R&D pharmacologist at AstraZeneca (U.S.). I subsequently did a DPhil (PhD) in neurophysiology at the University of Oxford and then a postdoctoral stint at the University of Queensland, Australia. It was then that I decided I wanted to work in biotech or pharma, bringing cutting edge therapeutic products to market.

However, I took a detour. After the postdoc, I transitioned into intellectual property law, becoming a registered patent and trademark attorney at an intellectual property (IP) law firm. As a patent attorney you encounter innovation daily, which made me want to pursue a more hands-on role in biological innovation.

I moved into technology transfer at a major Australian university, working in IP management, technology commercialization and startup creation at the Institute for Molecular Bioscience at the University of Queensland. Then I joined Sanofi’s consumer healthcare division, where I led medical innovation efforts and gained hands-on clinical trial experience. Later, I returned to the U.K. to join a gene editing company in an innovation role. This company was acquired by PerkinElmer (now Revvity).

What drew me to Pencil is the chance to build something genuinely innovative and disruptive, an editor created from the ground up with capabilities/features designed for therapeutic editing to create products that meaningfully improve patients’ lives.

Q: What are the current shortcomings of gene editing approaches?

Smith: Today’s gene editing field is dominated by technologies like CRISPR, base editing, and prime editing—remarkable tools that have transformed biological and medical research. But when you take these systems out of the lab and try to apply them therapeutically, significant limitations are revealed.

The first challenge is that most current editing technologies require a nick or double-strand break in the DNA to make an edit —a process which can introduce errors. A double-strand break severs the DNA completely, while a nick breaks a single strand. The cell can make errors while trying to repair DNA breaks, ranging from unwanted inserts or deletions (indels) to much more serious effects such as major genome changes like duplicating or deleting whole chromosomes (aneuploidy), and major shuffling of the genomic DNA (translocations and chromothripsis). In addition, treated cells in the same tissue may repair the break differently, leading to a range of indels with only a proportion of those cells bearing the desirable outcome.

A second challenge is that limited specificity of guide RNAs (gRNAs) can generate unwanted off-target edits. Conventional CRISPR-Cas9 systems are particularly known for this, and even newer CRISPR modalities don’t fully escape the issue of editing at unintended sites. The technical issue is due to the directionality of RNA synthesis and increased error rates associated with longer gRNAs.

Another challenge is that short DNA sequences called PAM sites, which tell the system, “This is the right spot to cut,” are not distributed evenly across the genome, meaning many therapeutically relevant positions are simply inaccessible. Therefore, current editing tools can lack flexibility to reach—and correct—some mutations.

So, while current editors have opened extraordinary scientific doors, the challenges of DNA breaks, off-target effects, and other shortcomings severely constrain their therapeutic potential.

Q: Pencil Biosciences intends to reinvent gene editing. How are you doing it, and what advantages does your approach offer over existing technologies?

Smith: Rather than mining nature for new editors, as the field has traditionally done, Pencil has taken a fundamentally different approach: we are designing gene editors from scratch.

Gene editors are generally composed of multiple functional elements. We’ve been engineering these elements individually, each with a single, well-defined function, and then assembling them into working editor prototypes. Our overarching goals from day one have been to create radically smaller editors that can be customized to the required edit, with the goal of enabling efficient in vivo delivery and ultimately supporting the creation of safer, more flexible therapies.

One of our lead prototypes is called Break-Free^TM, and even at this early stage, it shows several promising advantages. Our Break-Free approach edits DNA without creating a nick or double-strand break. By avoiding any physical cut in the genome, we reduce the risk of DNA damage and the associated mutations that arise when cells attempt to repair that damage.

Together, the customizable nature of the editor and break-free mechanism give our system a very different profile compared to existing technologies.

Q: Can you describe the foundation of Pencil’s platform? What makes it uniquely powerful or versatile compared with CRISPR or base editing?

Smith: When we designed the individual components of our system, we ensured that each performed only one job. That modularity gives Pencil editors several important advantages.

Our targeting elements do not rely on PAM sites or other natural docking sequences. Because these components are fully synthetic, we can design them to reach essentially any genomic location. That gives us access to target sites that CRISPR-based systems can never reach.

Pencil’s system is also intrinsically modular. In our case, if we want to change the function, we simply swap out one effector for another—a process akin to configuring Lego^® bricks— and the editor stays compact.

This Lego brick modularity allows us to tune our targeting elements to be [either] extremely specific for a single site or be more permissive, depending on the therapeutic need. That level of programmable specificity is possible because we are not constrained by natural biology.

Altogether, those features make the platform uniquely flexible, scalable, and potentially safer.

Q: How do you see Pencil’s technology expanding the reach of genetic medicine beyond what’s possible today?

Smith: Our technology can become an important new addition to the gene editing toolkit, especially because safety and precision are absolutely critical.

Development of a safer editor may eventually broaden the patient population eligible for genetic medicine. Today, because risks are high, gene therapies are restricted to patients who are extremely ill or have no alternatives. If safety improves and dosing flexibility increases, we could begin treating chronic but non-fatal diseases. For example, hypercholesterolemia or autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and type 1 diabetes, where improving quality of life is just as important as extending it.

There’s still much to learn, and we are actively thinking about how best to move this technology forward into the clinic, with such exciting possibilities motivating our work.

Q: What kind of team and culture are you building at Pencil to drive innovation and attract top scientific talent?

Smith: Our mission naturally attracts exceptional people. The work is technically very challenging and that inspires a forward-thinking, resilient kind of scientist who wants to push boundaries.

Culturally, my goal is to empower the team, giving them the belief that this ambitious effort is possible, while also grounding our work in deliverables and accountability. Innovation must coexist with disciplined execution, especially in a startup with finite resources.

Ultimately, the team is here because we believe this technology can help patients with chronic or incurable diseases. Keeping this purpose front and center inspires us as we push the science forward.

Q: What milestones or partnerships are you most excited about as we progress through 2026?

Smith: In the near term, our focus is on generating proof-of-concept data in T cells and other therapeutically relevant cell types, such as hematopoietic stem cells, and this next phase of validation is crucial.

Once we have that foundation, we look forward to forming strategic partnerships with pharmaceutical and biotech companies who want to explore safer and more customizable editing tools for therapeutic development. Collaborations will be key, not only to validate the technology externally but to fully explore its capabilities and accelerate translation into actual therapies.

We will also be raising capital in 2026. That will be an important step as we scale the work.

Damian Doherty has been in media and publishing for over 30 years, beginning at News Corporation. Damian has managed, edited, and launched life science titles in drug discovery and precision medicine. He was features editor of Drug Discovery World and founded the Precision Medicine Leaders Summit and the Journal of Precision Medicine. He edited AIMed magazine before launching Photo51Media, a platform for illuminating untold, compelling stories in precision healthcare. Damian joined Mary Ann Liebert in 2021 to help steer the new rebrand and relaunch of Clinical OMICS to Inside Precision Medicine.